Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression

Abstract

High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.

Mesothelioma: recent highlights

“…We found that therapeutic levels of aspirin and its metabolite salicylic acid suppress the growth, migration, invasion, wound healing, and anchorageindependent colony formation of HMGB1-secreting human mesothelioma cells. Moreover, in vivo, aspirin significantly inhibited mesothelioma growth in a xenograft model (21). These findings illustrated a novel mechanism by which aspirin may exert its anti-tumorigenic properties (e.g., HMGB1 inhibition) while remaining consistent with its well-described anti-inflammatory properties.…”

Aspirin’s Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses

“…This is desirable because clinical management of injury requires specific attenuation of sterile inflammation, without compromising innate immunity against pathogens. Likewise, SA inhibits the cancer-promoting activities of HMGB1 in mesothelioma, whose cells are addicted to HMGB1 for growth and survival (41).…”

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

“…Migration and invasion of malignant mesothelioma cells are inhibited by aspirin via a high-mobility group box 1 (HMGB1)-mediated mechanism; HMGB1 is an inflammatory molecule involved in the initiation and progression of this tumor type [71]. Interestingly, in vitro and in vivo studies show that aspirin not only has a relevant role in the prevention of breast carcinogenesis, but also exerts growth-inhibitory effects on breast CSCs through the reprogramming of the mesenchymal-epithelial transition, a mechanism leading to the metastatic potential of advanced breast tumors [72].…”